Patients with metastatic colorectal cancer (MCRC) harboring BRAF V600E mutations benefited from first-line treatment with the targeted therapies encorafenib and cetuximab plus an MFOFOFOX6 chemotherapy regimen, according to results from the Phase III breakthrough trial led by researchers at the University of Texas MD Anderson Anderson Cancer Center.
The findings, presented today at the American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium and published in Nature medicinedemonstrated an overall response rate of 60.9% (ORR) with the three-drug combination compared to 40% with standard of care (SOC): chemotherapy with or without bevacizumab. In the experimental arm, 68.7% of patients had a duration of response of at least six months, compared to 34.1% of patients in the SOC arm.
Data from this multi-institutional collaboration in 28 countries supported accelerated approval of this combination by the Food and Drug Administration (FDA) in December 2024, providing a new effective first-line treatment option for patients with BRAF V600E mutant MCRC .
“Chemotherapy has had limited effectiveness as a first-line treatment in controlling the aggressive tumor growth we see in patients with this mutation,” said co-lead investigator Scott Kopetz, MD, Ph.D. Chair of Translational Integration at MD Anderson. “This new regimen highlights the importance of combining dual-targeting therapy with chemotherapy to improve patient outcomes in the front-line setting, and durable responses are a significant development as we work to improve the quality of life of these patients.” patients.”
According to the National Cancer Institute, more than 150,000 people are diagnosed with colorectal cancer, making it the fourth most common cancer in the United States. BRAF mutations occur in approximately 8-12% of cases and are associated with aggressive tumor growth, low efficacy of SOC treatments, and poor prognosis, with a median overall survival of less than 12 months. Previously, there were no approved first-line targeted therapies for patients with BRAF V600E mutant MCRC.
The Breakwater trial was one of the first studies to use the FDA’s blueprint, an initiative to encourage evaluation of therapies in earlier clinical settings for advanced cancers rather than after patients received numerous prior treatments.
The trial enrolled patients who were at least 16 years of age with previously untreated BRAF V600E mutant MCRC. Patients were equally randomly assigned to one of three treatment arms: SOC chemotherapy with or without bevacizumab; a dual combination of encorafenib plus cetuximab; or a triple combination of encorafenib, cetuximab and mfolfox6.
When researchers analyzed the subgroups of patients in the trial, the triple combination showed benefits among important groups, including patients whose cancer spread to three or more organs and those with liver metastases.
“These results support this combination as a new first-line standard of care for patients with BRAF V600E mutant metastatic colorectal cancer,” Kopetz said. “It also highlights the importance of rapidly identifying the molecular subtypes of colorectal cancer at diagnosis to optimize treatment strategies for our patients.”
The safety profile of this combination was consistent with the known safety profile of each respective drug. No new safety signals were identified. The most common adverse reactions included nausea, rash, fatigue, vomiting, abdominal pain, diarrhea, and decreased appetite, all of which were reported in at least 25% of patients and were similar between arms.
Final estimates of progression-free survival and overall survival will be formally evaluated in the next phase of the trial. Future analyzes of this trial may shed light on predictive biomarkers for this combination therapy.
The study was sponsored by Pfizer Inc., and Kopetz consulted for Pfizer and received research funding from the company.